1. Field of the Invention
This invention relates to a method for preparing 5,6-dihydroxyindole. More particularly, this invention relates to a one step process for preparing 5,6-dihydroxyindole from 4,5 dihydroxy-2,.beta.-dinitrostyrene in high yields and purity by a catalytic reductive cyclization in the presence of hydrogen and a supported palladium, platinum or rhodium catalyst. The invention also relates to the preparation of the starting 4,5-dihydroxy-2,.beta.-dinitrostyrene reactant and the reaction intermediates therefor.
2. Discussion of the Prior Art
5,6-dihydroxyindole is a known intermediate in the preparation of melanin which is an organic pigment useful in, for example, hair dye preparations. Hair dyeing compositions and methods using 5,6-dihydroxyindole or a derivative thereof are shown, for example, in U.S. Pat. Nos. 2,934,396 and 3,194,734. The hydroxyindoles are also known as anti-oxidants, see e.g. U.S. Pat. No. 2,787,551, and as intermediates in the production of amino acids, alkaloids, tryptamines, and the like, see e.g. U.S. Pat. No. 3,732,245. For these various utilities, it is essential that the 5,6-dihydroxyindole be available in high purity and under stable conditions.
Therefore, the synthesis of indoles and hydroxyindoles has received much attention, due to their broad range of uses and biological applications. In particular, extensive studies have been made of the synthesis of 5,6-dihydroxyindole and its subsequent polymerization to melanin. See, for example, Mason, H. S., J. Biol. Chem, 1948, Vol. 172, p. 83; Bu'Lock, J. D. and Harley-Mason, J., J. Chem. Soc. 1951, p. 703 and p. 2249; Cromartie, R. I. T. and Harley-Mason, J., J. Chem. Soc. 1953, p. 200; Beer, R. J. S., et al, J. Chem. Soc. 1948, p. 2223; Clemo, G. R. and Weiss, J., J. Chem. Soc. 1945, p. 702 and p. 1795; Clemo, G. R. and Duxbury, F. K., J. Chem. Soc. 1952, p. 3464 and p. 3844; Benigni, J. D., et al, J. Heterocycl Compounds, 1965, Vol. 2, p. 387; and Young, T. E., et al, J. Org. Chem. 1980, Vol. 45, p. 2901. The chemical reductive cyclization of 5-benzyloxy-2,.beta.-dinitrostyrene to 5-benzyloxyindole using powdered iron and organic acid is shown in Canadian Pat. No. 555,760. The reductive cyclization of ortho-nitro-.beta.-aminostyrene to the corresponding indoles by either chemical (e.g. Fe.degree.--CH.sub.3 CO.sub.2 H) or catalytic (e.g. H.sub.2 --Pd/C, organic solvent) reduction is shown in U.S. Pat. No. 3,732,245. These syntheses, however, are unattractive either because of low yields or the results are difficult to reproduce on a large scale.
The isomeric 4,5-dihydroxy-2,.beta.-dinitrostyrenes are promising intermediates in the synthesis of 5,6-dihydroxyindole. Foe example, in the above cited article by Beer, et al, acetylation, chemical reductive cyclization (Fe.degree.--CH.sub.3 CO.sub.2 H) and deacetylation give about 35% yield as shown in the following Scheme I. ##STR1##
However, this scheme, in addition to requiring the acetylation and deacetylation steps to protect and then unblock the hydroxyl groups also requires a complicated cyclization using elemental iron, Fe.degree., and acetic acid. Still further, stringent purification is required to isolate the intermediate 5,6-diacetoxyindole (6) from the resulting black gum. 5,6-Dihydroxyindole (7) resulting from the deacetylation of 5,6-diacetoxyindole is unstable under the reaction conditions (pH&gt;7), and antioxidants (e.g. Na.sub.2 S.sub.2 O.sub.4) must be included. Accordingly, the product 5,6-dihydroxyindole ideally is not used directly for the production of melanin.
Other researchers have shown the efficacy of AlX.sub.3 --thiol and AlCl.sub.3 --dichloroethane systems in the cleavage of methylenedioxy ethers. See, for example, M. Node, et al, J. Org. Chem. 1980, Vol. 45, p. 4275; and M. A. Avery, et al, J. Org. Chem., 1980, Vol. 45, p. 2750, respectively. In the latter procedure, which uses a ring opening method, 4,5-dihydroxy-2-nitrobenzaldehyde (1) is synthesized from 6-nitropiperonal (9) ##STR2## 5-chloromethoxy-4-hydroxy-2-nitrobenzaldehyde (10), ##STR3## in 87.9% reported yield based on 6-nitropiperonal. Although a one-step demethylenation of 6-nitropiperonal with AlCl.sub.3 --ClCH.sub.2 CH.sub.2 Cl seems viable, the desired product (1) is isolated in higher yield through the intermediary (10). 4,5-dihydroxy-2-nitrobenzaldehyde (1) can then be converted to 4,5-dihydroxy-2,.beta.-dinitrostyrene (2) by known procedures, such as shown by Beer, et al. However, it has been found that the dechloromethylation of Avery, et al cannot be effectively utilized for amounts of starting material in excess of about 1 gram.
Alternate routes to (E)-4,5-dihydroxy-2,.beta.-dinitrostyrene are also known. Thus, condensation of 3,4-dialkoxybenzaldehydes with CH.sub.3 NO.sub.2, followed by nitration, gives the corresponding 4,5-dialkoxy-2, .beta.-dinitrostyrene. However, standard ether cleavage with hydrogen halides is not useful, since hydrohalogenation occurs. It was necessary, therefore, to develop a mild method for removal of the protecting groups. Although trifluoroacetic acid (CF.sub.3 CO.sub.2 H) has been reported as a debenzylation reagent (March, J. P. and Goodman, L., J. Org. Chem. 1965, Vol. 30, pp. 2491-2) the authors do not elucidate on the general theory or scope of the debenzylation reaction or on its advantages. For example, it has now been found that other groups in the molecule can increase the rate of debenzylation, but these groups are not necessary for the success of the reaction. It has also now been found that CF.sub.3 CO.sub.2 H is 100% selective and does not affect other functional groups in this molecule. Based on this discovery, a mild and selective method for unblocking the hydroxyl protecting benzyl grouos has now been developed using trifluoroacetic acid as the selective debenzylation agent. According to this reaction, the benzyl groups of 4,5-dibenzyloxy-2,.beta.-dinitrostyrene are removed without reduction of the nitro groups or addition to styrene double bond as would occur with normal ether cleavage reagents (e.g. H.sub.2 --Pd/C, hydrogen halides, and H.sub.2 SO.sub.4). Accordingly, a highly effective and novel means has been developed to prepare the 4,5-dihydroxy-2,.beta.-dinitrostyrene compound used as the reactant for forming the object 5,6-dihydroxyindole by the selective debenzylation of 4,5-dibenzyloxy-2,.beta.-dinitrostyrene with trifluoroacetic acid.
Previously, catalytic cyclization of 4,5-dihydroxy-2,.beta.-dinitrostyrene (14) was unknown, although several methods are known for the corresponding dialkoxy and diaryloxy derivatives. See, for example, the above mentioned article by J. D. Benigni, et al and C. F. Heubner, et al, J. Amer. Chem. Soc. 1953, Vol. 75, pp. 5887-5890. However, these procedures which involve refluxing CH.sub.3 CO.sub.2 H--Fe.degree. and 10% Pd/C--H.sub.2 in organic solvents, e.g. a mixture of ethyl acetate, acetic acid, and ethanol, are not useful for cyclization of 4,5-dihydroxy-2,.beta.-dinitrostyrene (14). Under the typical H.sub.2 pressure range of from 40 to 55 pounds per square inch (psi) the cyclization of 4,5-dihydroxy-2,.beta.-dinitrostyrene gives only a small amount of 5,6-dihydroxyindole which is contaminated with many by-products.